Lithium’s Neuroprotective Role in Treating Neuropsychiatric Disorders

The scientific paper by Diniz et al., titled Lithium and Neuroprotection: Translational Evidence and Implications for the Treatment of Neuropsychiatric Disorders, explores the growing evidence that lithium—a well-known mood stabilizer—may also offer protective benefits for the brain. Published in Neuropsychiatric Disease and Treatment in 2013, the study reviews both preclinical and clinical research to examine lithium’s potential role in preventing or slowing neurodegenerative diseases, particularly Alzheimer’s disease. By analyzing how lithium interacts with key biological pathways, such as the inhibition of glycogen synthase kinase-3β (GSK-3β), the paper highlights lithium's ability to reduce neuroinflammation, decrease toxic protein buildup, and support brain cell survival.

Lithium is best known as a mood stabilizer for people with bipolar disorder. It has been safely used in psychiatry since the late 1940s. Over time, doctors noticed something interesting—patients who took lithium for many years seemed less likely to develop Alzheimer’s disease (AD). This sparked curiosity among researchers: Could lithium do more than treat mood disorders? Could it also protect the brain?

This scientific study reviews how lithium affects the brain and why it might slow down or even prevent damage caused by neurodegenerative diseases like Alzheimer’s. It explains the biological changes lithium causes, reviews results from animal tests and human studies, and explores the idea of lithium as a long-term brain-protective treatment.

The study authors explain their goal clearly: “This article aims to review the presumed mechanisms by which lithium may exert its neuroprotective effects and how such mechanisms may help to delay the progression of AD.”

To understand lithium’s role in brain health, the researchers looked at many different studies. These included:

• Laboratory studies using cells and brain tissue to see how lithium affects proteins and enzymes.
• Animal studies where mice with Alzheimer's-like symptoms were treated with lithium.
• Clinical research in people with bipolar disorder, mild cognitive impairment (MCI), or early Alzheimer’s.
• Brain scans and blood tests to see physical and chemical changes in the brain caused by lithium.

Combining this wide range of research, the authors found many links between lithium and brain-protective effects.

Lithium works by affecting certain chemical processes in the brain. One major action is blocking an enzyme called GSK-3β. This enzyme is involved in harmful changes in brain cells, like the buildup of tau protein and amyloid-β42, which are key features of Alzheimer’s disease.

In the study, the authors state, “Evidence from preclinical studies suggests that neuroprotection induced by lithium is mainly related to its potent inhibition of the enzyme glycogen synthase kinase-3β (GSK-3β).”

Lithium blocks this enzyme in two ways:

1. Directly, by competing with magnesium and interfering with how the enzyme works.
2. Indirectly, by activating other proteins that stop GSK-3β from working.

By reducing GSK-3β activity, lithium helps prevent brain cell damage and may slow Alzheimer’s progression.

Lithium also boosts autophagy, the brain's way of cleaning harmful proteins. The study notes that lithium “decreases inositol triphosphate formation and, in turn, stimulates the autophagic processes in neurons.” This means harmful proteins like amyloid-β42 are cleared out more effectively.

In cell and animal studies, lithium has shown many helpful effects:

• Reduces harmful proteins: Lithium lowers the levels of both tau and amyloid-β42. This helps protect neurons from damage.
• Supports brain cell survival: It increases the production of anti-apoptotic proteins like Bcl-2, which help prevent cells from dying.
• Encourages brain cell growth: Lithium helps stimulate neurogenesis, and the growth of new brain cells, especially in the hippocampus—an area important for memory.

The paper explains: “These neuroprotective effects of lithium are mediated, at least in part, by the inhibition of GSK-3β activity in neurons.”

In Alzheimer’s mouse models, lithium not only reduced brain damage but also improved memory. Mice treated early with lithium had better results than those treated later. The study emphasizes that “treatment when started earlier… had a significantly stronger effect in reducing AD-related neuropathology and memory impairment.”

Another key point is that lithium stimulates neurotrophic factors like BDNF and VEGF, which help neurons grow, stay strong, and connect better.

Studies in people also support lithium’s protective effects. Many of these were done with bipolar disorder patients, who often take lithium long-term.

The study reports: “Case registry studies found a lower risk for incident dementia, in particular of AD, in bipolar patients after long-term lithium use.” In one observational study, older adults with bipolar disorder who took lithium had about the same risk for Alzheimer’s as people without bipolar disorder, suggesting lithium may reduce that risk.

People on lithium also had:

• Improved memory scores on tests like the Mini-Mental State Examination (MMSE)
• Higher brain volumes, including in the hippocampus and amygdala
• Increased levels of BDNF, which supports brain cell health

A clinical trial in people with mild cognitive impairment found that even very low doses of lithium (called microdoses) helped stabilize memory and reduce a harmful protein called phosphorylated tau. One exciting detail: “Amnestic MCI subjects on the lithium regimen presented stable cognitive performance and lower conversion rates to AD compared to subjects on placebo.”

However, not all studies showed clear results. Some were too short or had high dropout rates. One 10-week trial found no major changes in memory or protein levels, though it did find increased BDNF in some people with better thinking scores.

Lithium also lowers inflammation and oxidative stress, harming brain cells over time. It reduces chemicals like interleukin-1β and tumor necrosis factor-α, which cause inflammation in the brain.

The study says: “Chronic lithium treatment can attenuate arachidonic acid production, an essential feature of unspecific inflammatory response.” This helps calm the immune response in the brain, which can otherwise make diseases like Alzheimer’s worse.

The study gives strong evidence that lithium could help prevent or slow Alzheimer’s disease. It supports brain health by:

• Reducing harmful proteins (like tau and amyloid)
• Boosting brain cell survival and growth
• Helping the brain clear out waste
• Lowering inflammation and stress

But scientists still don’t recommend lithium for Alzheimer’s treatment—at least not yet. That’s because more research is needed to find the safest and most effective doses and to understand which patients benefit most.

Lithium does have side effects, especially in older adults. These include upset stomach, tremors, kidney changes, and low thyroid hormone levels. However, the study points out that “subtherapeutic doses of lithium… were safe and there were no significant changes in laboratory parameters related to renal and thyroid function.”

This means small amounts might help the brain while avoiding most side effects—but more studies are needed.

This scientific paper gives hope that lithium might one day be used to protect the brain from Alzheimer's disease and possibly delay its progress. It shows how lithium affects essential brain chemicals, supports healthy brain cells, and lowers inflammation and stress. Both lab studies and human research show promising results, especially when lithium is used over the long term and in low doses.

However, lithium is not yet approved for Alzheimer's prevention or treatment. More large-scale, long-term studies are needed to confirm how well it works and to find the safest way to use it. Until then, lithium remains a powerful medicine for mood disorders—and an exciting candidate in the search for new ways to protect the brain.